A non-manufacturer-sponsored, retrospective study to assess 2-year safety outcomes of the BellaGel® SmoothFine as compared with its competitors in the context of the first Korean case of a medical device fraud

Background We conducted this study to assess preliminary 2-year safety outcomes of an implant-based augmentation mammaplasty using the BellaGel® SmoothFine in the context of the first Korean case of a medical device fraud. Methods Our clinical series of the patients (n = 579; 1,158 breasts) received augmentation using the BellaGel® SmoothFine, Naturgel™, Motiva Ergonomix™, Eurosilicone Round Collection™, Natrelle® INSPIRA™, Natrelle® 410, Mentor® MemoryGel Xtra or Microthane®. The patients were evaluated for incidences of postoperative complications and Kaplan-Meier survival and hazards. Results Overall, there were a total of 101 cases (17.4%) of postoperative complications; these include 31 cases (5.4%) of shape deformity, 21 cases (3.6%) of CC, 18 cases (3.1%) of early seroma, 8 cases (1.4%) of infection, 5 cases (0.9%) of early hematoma, 1 case (0.2%) of delayed hematoma, 1 case (0.2%) of rupture and 1 case (0.2%) of ripping. Moreover, there were also 15 cases (2.6%) of other complications. There were significant differences in incidences of postoperative complications between the breast implants from different manufacturers (P = 0.034). The Natrelle® 410 showed the longest survival (333.3±268.2 [141.5–525.1] days). A subgroup analysis showed that there were no significant differences in incidences of postoperative complications between the breast implants (P = 0.831). Moreover, the Natrelle® INSPIRA™ showed the longest survival (223.7±107.1 [-42.3–489.6] days). Conclusions Here, we describe preliminary 2-year safety outcomes of an implant-based augmentation mammaplasty using the BellaGel® SmoothFine in the context of the first Korean case of a medical device fraud.

Introduction circulated in the Korean market. Of these, 114,365 textured devices were the Allergan products and only 4,560 were from a Korean manufacturer, the HansBiomed Co. Ltd. Due to concerns for a causal relationship between a textured breast implant and the occurrence of BIA-ALCL, a textured device cannot be further used in Korea, as mandated by the KMFDS [13].
The global breast implant industry has faced a crisis, thus termed as a breast implant crisis. A breast implant crisis was further classified into the first crisis (Dow Corning), the second crisis (Poly Implant Prothèse [PIP]) and the third crisis (BIA-ALCL) [14,15].
Recently in Korea, plastic surgeons, manufacturers of silicone gel-filled breast implant and patients have also faced a breast implant crisis [10,11,13]. Between 2019 and 2020 (August 16 and December 24, 2019 and October 5, 2020), a total of 3 cases of BIA-ALCL occurred in Korea. This warned stakeholders in the breast implant industry in Korea that they would face a crisis due to an implant failure. Indeed, the clinical use of textured breast implants was banned by the KMFDS in August 29, 2019. Then, they were forced to respond to a question regarding a possible causal relationship between a microtextured surface of the device and a risk of BIA-ALCL in Korea [11]. As reported by Kim JH, however, the first Korean case of a medical device fraud was committed by the manufacturer of the BellaGel 1 implants including the BellaGel 1 SmoothFine. According to the news media, a Korean manufacturer, the Hans-Biomed Co. Ltd., was investigated by the Korean police for using unapproved substances, such as 7-9700 and Q7-4850, and deliberately modifying the shell structure from 5 to 4 layers during the manufacturing process [10,11].
To date, attempts have been made to compare the safety between the breast implants from different manufacturers in Korea [16,17]. That is, Nam SY, et al. compared the vulnerability to capsular contracture (CC) based on surface properties between the BellaGel 1 implants, including the BellaGel 1 SmoothFine, and the Motiva Ergonomix TM SilkSurface. These authors drew conclusions that the BellaGel 1 SmoothFine was the least vulnerable to CC of the sample devices [16]. Moreover, Yoon S and Chang JH compared 1-year safety outcomes between the devices from 6 different manufacturers, thus reporting that the BellaGel 1 SmoothFine is not inferior to its competitors [17].
Given the above background, we conducted this study to assess preliminary 2-year safety outcomes of an implant-based augmentation mammaplasty using the BellaGel 1 SmoothFine as compared with its competitors in the Korean market in the context of the first Korean case of a medical device fraud.

Study patients and setting
The current multi-center, retrospective, observational study was conducted in a total of 715 patients (n = 715) who underwent augmentation mammaplasty using breast implants at our hospitals between September 26, 2017 and October 21, 2019.
Inclusion criteria for the current study are as follows: We therefore evaluated a total of 579 patients (n = 579) in the current study.

Ethics statement
The current study was approved by the Internal Institutional Review Board of the Korea National Institute of Bioethics Policy; it was conducted in compliance with the relevant ethics guidelines. Written informed consent was waived due to its retrospective nature.

Patient evaluation and criteria
In the current study, the patients' characteristics and survival of breast implants were analyzed, as previously described [18,19]. We evaluated all the eligible patients (n = 579) depending on their baseline characteristics and complications. We also stratified them according to the age group (20-29, 30-39, 40-49, 50-59 and �60 years old), the length of follow-up period (<1 year and �1 year) and the trade name of breast implants. We classified breast implants as microtextured, round smooth and anatomical devices according to their shape and surface topography [20]. Then, we performed a comparative analysis of incidences of postoperative complications, cumulative complication survival and cumulative hazards. Postoperative complications were classified into implant-related and surgery-related ones.
Considering risk factors of developing complications of an implant-based augmentation mammaplasty, we performed a subgroup analysis of the patients' postoperative complications. According to some "Core" studies, incidences of CC were significantly higher in secondary cases, such as revision surgery or reoperation, as compared with primary ones [21][22][23][24]. Moreover, it has been reported that there is a significant correlation between the use of anatomical implants and lower incidences CC [25]. Furthermore, locations of the implant pocket also serve as risk factors of developing CC; a subglandular pocket is commonly associated with higher incidences of CC as compared with a submuscular or dual-plane one [26]. We therefore excluded such factors as secondary cases, anatomical devices and subglandular pocket in comparing incidences of postoperative complications between the subgroups.

Statistical analysis of the patient data
Values were expressed as the number of the patients with percentage, mean±SD (SD: standard deviation) or mean±SE (SE: standard error), where appropriate. Continuous variables were analyzed using the repeated measures analysis of variance (ANOVA), the Kruskal-Wallis test or Fisher's exact test. Non-continuous variables were analyzed using the χ 2 -test. The cumulative overall complication-free survival was estimated, for which 95% confidence intervals (CIs) were provided. Moreover, differences in complication-free survival between the breast implants were tested for statistical significance using the repeated measures analysis of variance (ANOVA) and Duncan's post-hoc analysis. Furthermore, the corresponding Kaplan-Meier survival and hazards were plotted as a curve. Statistical analysis was done using the SPSS ver. 18.0 for windows (SPSS Inc., Chicago, IL). A P-value of <0.05 was considered statistically significant.

Baseline characteristics of the patients
The study population comprises a total of 715 patients (n = 715) who received an implantbased augmentation mammaplasty at our hospitals, 579 of whom met inclusion/exclusion criteria. All the eligible patients were Korean women with a mean age of 33.1±8.1 years old, who were followed up during a mean period of 218.4±153.2 days. Our clinical series of the patients include 578 bilateral cases and 1 unilateral case. We therefore evaluated a total of 1,157 breasts (578 left breasts and 579 right breasts). Baseline characteristics of the patients are represented in Table 1. Of these patients, a total of 503 (n = 503) were evaluated on a subgroup analysis. Disposition of the study patients is shown in Fig 1. Of a total of 715 patients, 579 (n = 579) met inclusion/exclusion criteria. There were 67 patients (n = 67) receiving revision or reoperation, 13 (n = 13) receiving anatomical or textured breast implants and 5 (n = 5) receiving a device in the subglandular pocket. But 4 patients (n = 4) received revision or reoperation using anatomical or textured breast implants and 5 (n = 5) received revision or reoperation using a device in the subglandular pocket. A total of 503 patients (n = 503) were therefore evaluated on subgroup analysis.
As shown in Table 5, there were significant differences in incidences of postoperative complications between the age groups; there were age-dependent increases in them (P<0.05). But there were no significant differences in incidences of postoperative complications between the two groups divided based on a cut-off value of 1 year (P>0.05) ( Table 6).
Incidences of postoperative complications by the trade name of breast implants are represented in Table 7. This showed that there were significant differences in incidences of postoperative complications between the breast implants (P<0.05). Of note, incidences of CC were significantly higher in the patients receiving the Naturgel™ (4.0%, 8/199)

Results of a subgroup analysis
According to a subgroup analysis of incidences of postoperative complications, there were no significant differences in them between the breast implants (P>0.05) (

Discussion
Since the introduction of a silicone gel-filled breast implant to augmentation mammaplasty, plastic surgeons and manufacturers of a device experience a transition from the previous generation of the device to the next generation of one. Thus, there has been an evolution in the breast implant design in an effort not only to improve aesthetic outcomes of an implant-based augmentation mammaplasty but also to minimize the occurrence of its complications [27]. Contemporary silicone gel-filled breast implants are characterized by increased surface roughness due to the modification to the shell surface. It remains problematic, however, patients receiving an implant-based augmentation mammaplasty are vulnerable to its long-term complications despite improvements in design and technology of a silicone gel-filled breast implant. Indeed, there is a variability in the mode of interaction between a device and the soft tissue depending on its surface characteristics [20]. Surface modification may result from previous in vitro and clinical studies showing positive correlations between surgical results and surface topography [28,29]. Over the past decades, macrotexturization or microtexturization,  Reconstructive augmentation mammaplasty 0 (0.0%)  [28,30]. As nanotechnology has undergone technological advancements, a novel silicone gel-filled breast implant controlling cellular functions has emerged [31]. Moreover, it has also been used to improve the surface properties of a device. The Motiva Ergonomix™ VelvetSurface 1 is equipped with 1,800-2,200 contact points of 40,000-100,000 nm depth, being much narrower as compared with a macrotextured device. Moreover, the Motiva Ergonomix™ SilkSurface 1 is equipped with 49,000 contact points per 16,000 nm, being much smaller and shallower depressions as compared with a macrotextured or microtextured device [31]. Of note, according to the latest International Standards Organization (ISO) 14607:2018 definition, the Motiva Ergo-nomix™ SilkSurface 1 is classified as the smooth breast implant [32]. Thus, manufacturers of a breast implant continue to use diverse methods for the development of a novel device for the purposes of stabilizing the device in the pocket by increasing the coefficient of friction or improving the integration of the device into the tissue [33]. It would therefore be mandatory  to refine current best practices in an implant-based augmentation mammaplasty considering the unique features of diverse types of a device [34].

Profile of breast implant
To date, the breast implant industry in Korea has experienced a transition from a textured device to a microtextured one. This is well illustrated in the current results showing that 94.8% of our clinical series of the patients received microtextured devices. Indeed, use of textured breast implants was banned by the KMFDS in Korea [11]. In other countries, plastic surgeons have moved towards smooth breast implants and manufacturers of a device and regulatory agencies discontinued the supply of textured devices in an effort to reduce risks of developing BIA-ALCL [35]. As shown in the current study, the Naturgel™, the BellaGel 1 SmoothFine and the Motiva Ergonomix™ are representative popular brands of a microtextured breast implant. Of these, the BellaGel 1 SmoothFine and the Motiva Ergonomix™ were compared for 1-year safety outcomes in a recent published study. This showed that CC occurred at a higher incidence in the patients receiving the BellaGel 1 SmoothFine as compared with those receiving the Motiva Ergonomix™ (2.27% vs. 0.00%, P<0.05) [19]. This is in agreement with the current results; CC occurred at an incidence of 4.1% and 2.7% in the corresponding order.
According to a review of the previous published literatures, several studies have also been conducted to compare between the breast implants from different manufacturers in other countries [36][37][38][39][40]. These studies have reflected a transition from a round breast implant to an anatomical device or superiority of one anatomical device to another irrespective of whether they are retrospective or prospective in nature. We have efficiently used HRUS in performing a regular follow-up of our clinical series of the patients in a non-manufacturer-sponsored setting although the US FDA recommends that patients receiving a breast implant be further evaluation on magnetic resonance imaging scans at 3 years postoperatively and at a 2-year interval, and thereafter [17]. This is a different feature from previous comparative studies. The role of HRUS in examining the integrity and rotation of a breast implant has been of increasing interest [39,[41][42][43][44][45][46][47][48]. Moreover, its role has been expanded to manage patients who are suspected of having BIA-ALCL as well as to examine a breast mass [49,50]. In this regard, plastic surgeons are required to make an HRUS-assisted approach to an implant-based augmentation mammaplasty. To do this, the following 2 matters should be considered: (1) Information about a breast implant (e.g., location, constituents, shell, shape and manufacturer) and (2) Possible occurrence of implant-related complications (e.g., folding with or without detachment,  periprosthetic fluid collection, thickened capsule, rupture, capsular mass, malrotation of an anatomical device, upside-down rotation and foreign body reactions) [11].
Two-year safety outcomes of an implant-based augmentation mammaplasty using the Bel-laGel 1 SmoothFine should be interpreted in the context of the first Korean case of a medical device fraud. Since 2009, the HansBiomed Co. Ltd. has illegally used unapproved substances, such as 7-9700 and Q7-4850, while manufacturing the BellaGel 1 implants for the purposes of overcoming the detachment between the shell and gel of the device (Fig 11) [10].
In vivo use of 7-9700 is not permitted; it has been tested for cytotoxicity, skin irritation and skin sensitization, but no data has been obtained for mutagenicity/genotoxicity, pyrogenicity There is another problem that 7-9700 has been tested for cytotoxicity, skin irritation and skin sensitization without being tested mutagenicity/genotoxicity, pyrogenicity and system toxicity. Furthermore, In vivo use of Q7-4850 for >30 days is not also permitted [10]. Finally, the Hans-Biomed Co. Ltd. attempted to increase a soft feel of the BellaGel 1 SmoothFine by deliberately modified its shell structure from 5-to 4-layered shell in violation of the regulatory requirement enforced by the KMFDS. Although the BellaGel 1 SmoothFine with a 5-layered shell was approved by the KMFDS, the device with a 4-layered shell has also been circulated in the  Korean market, for which Kim JH provided evidence on HRUS [11]. In November 13, 2020, the KMFDS initiated the mandatory recall of the BellaGel 1 implants [10].
Illegal use of unapproved substance and the deliberate modification of the shell structure during manufacturing of the BellaGel 1 implants should be considered serious because the HansBiomed Co. Ltd. was previously involved in the PIP fraud by working as an original equipment manufacturer for the Rofil Medical International B.V. (Breda, Netherlands) that was a distributor of the M-Implants 1 rebranded from the PIP (Fig 12) [10].
The manufacturer of the BellaGel 1 implants was previously involved in the PIP fraud by working as an original equipment manufacturer for a distributor of the M-Implants 1 rebranded from the PIP.
The BellaGel 1 implants are non-FDA-approved products, although they have been described as a safe device according to manufacturer-sponsored studies [17,[51][52][53][54]. But their safety has become a mirage. Therefore, the safety of the BellaGel 1 implants, including the Bel-laGel 1 SmoothFine, should be stringently evaluated in an evidence-based manner.
There are no literatures indicating whether Korean plastic surgeons were aware of the manufacturer's previous involvement in the PIP fraud; even the corresponding author of 2 manufacturer-sponsored studies was involved in the development and design of BellaGel 1 implants, who is currently a non-executive medical director of the HansBiomed Co. Ltd. [10,52,54]. A 10-year prospective study was conducted to assess the efficacy and safety of the BellaGel 1 implants in August 24, 2010, for which 6-year interim results have been published [53]. This strongly suggests that some Korean patients might have received the BellaGel 1 implants that had been exported to Europe. Due to a lack of data about their composition that had not been characterized, such patients should be further evaluated for whether they had signs and symptoms indicating rupture or gel bleed. Moreover, it would also be mandatory to characterize the composition of the BellaGel 1 implants on explantation study in patients with rupture of the device after receiving the BellaGel 1 implants between August 24, 2010 and November 26, 2015 [10].

Surface topography of breast implant
Left breast   But limitations of the current study are as follows: First, we conducted the current study under the retrospective design at local clinics in Korea. Therefore, the possibility of selection bias could not be completely ruled out. Second, we followed up our clinical series of the patients for short periods of time. Third, the number of the patients receiving the Natrelle 1 INSPIRA TM (n = 4), the Mentor 1 MemoryGel Xtra (n = 13), the Microthane 1 (n = 3) or the Natrelle 1 410 (n = 10) is much smaller as compared with other breast implants. These differences may arise from the popularity of a microtextured device in Korea, surgeons' or patients' preference and a variability in the surgical cost, ranging from USD 3,535.39 to USD 7,090.78. Therefore, the possibility of comparison bias could not be completely ruled out. Fourth, we failed to control other confounding factors that may affect incidences of CC. It would therefore be difficult to make a direct comparison between the breast implants from different manufacturers. To date, no prospective randomized controlled trials have been conducted to standardize such factors [57]. Fifth, we failed to exclude the patients receiving a breast implant via a trans-axillary incision or a peri-areolar incision because they account for 95.0% (550/579) of total patients. It has been reported that use of a trans-axillary incision or a peri-areolar incision is associated with a higher risk of CC as compared with an inframammary fold (IMF) incision https://doi.org/10.1371/journal.pone.0259825.g008 [58,59]. In Asian patients, an IMF incision is not frequently used because it leaves a notable scar; a trans-axillary incision or a peri-areolar incision are frequently used in Asian countries where it is not recommended that a scar be left on the breast [60,61].